Nitric oxide (NO) signaling is essential for brain activity and normal neuronal function. Disrupted NO signaling is indicated as a potential underlying pathological event in several central nervous system (CNS) disorders and neurodegenerative scenarios. Molecular classes capable of enhancing NO related signaling cascades have shown utility in a variety of neurological disorders, including stroke, depression, and Alzheimer's disease (AD).
Nitrates, such as nitroglycerin and isosorbide dinitrate, mimic the action of NO and are known as NO mimetics. Nitrates have been used clinically for over 150 years as safe and effective treatments for acute angina. Some nitrates have demonstrated potential as therapeutics for several neurological disorders in preclinical animal models, especially for the treatment of AD. Unfortunately, the development of nitrates for neurodegeneration has faced challenges for several reasons. Generally, obstacles have centralized around the intrinsic physiochemical liability of the nitrate group itself, including: 1) poor metabolic stability; 2) challenges associated with precisely monitoring levels of NO mimetic activity (i.e., the logistical challenge of characterizing pharmacokinetics); and 3) nitrates are relatively unstable in the presence of atmospheric humidity (presenting a logistical challenge during manufacturing and storage prior to use).
Nitrates are suitable for use clinically as vasodilators in incidences of acute angina because this indication requires rapid onset of activity. Hence, the poor metabolic stability of nitrates is not a liability when used to treat acute angina. The chemical reactivity of nitrates prevents them from use clinically for the CNS, where sustained low level enhancement of NO signaling is desirable.
Furoxans are slow-acting NO mimetic neuroprotective and procognitive agents that can be used as AD therapies. (FIG. 1A.) Improved synaptic function has been demonstrated upon foruxan administration in cell cultures. Further, there is evidence of reduced AD pathological hallmarks upon treatment with these agents in cell cultures, which had previously been shown for nitrates but not furoxans. PRIOR ART FIG. 1B summarizes these furoxans for the CNS. However, the use of furoxans in CNS related animal models has not been demonstrated.
There is a need in the art for new treatments for neurological disorders. It would be advantageous to discover new furoxan compounds useful for treating various neurological disorders and conditions.